Dr Yaeger on the Efficacy of Adagrasib/Cetuximab in KRAS G12C+ mCRC

“The combined population [was] 94 patients, and the objective response rate by blinded independent [central] review was 34% and by investigator review was 43%—the responses were durable.”

Rona Yaeger, MD, associate attending physician, gastrointestinal medical oncologist, early drug development specialist, Memorial Sloan Kettering Cancer Center, details the efficacy of adagrasib (Krazati) plus cetuximab (Erbitux) in heavily pretreated patients with KRAS G12C–mutant metastatic colorectal cancer (mCRC).

Efficacy data from the phase 1/2 KRYSTAL-1 trial (NCT03785249) presented at the 2025 Gastrointestinal Cancers Symposium showed that among patients from the subgroup analysis treated with adagrasib/cetuximab (n = 94), the overall response rate (ORR) was 34% (95% CI, 25%-45%) per blinded independent central review (BICR) and 43% (95% CI, 32%-53%) per investigator assessment.

In June 2024, the FDA granted accelerated approval to adagrasib plus cetuximab for adult patients with KRAS G12C–mutant locally advanced or mCRC who received prior treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy.

In the open-label, nonrandomized, multi-cohort KRYSTAL-1 study, the best overall response per BICR and investigator review included complete response (0%; 0%), partial response (34%; 43%), stable disease (51%; 44%), progressive disease (6%; 5%), and not evaluable (9%; 9%). Of note, the disease control rate was 85% (95% CI, 76%-92%) and 86% (95% CI, 78%-92%) per BICR and investigator review, respectively. The median duration of response was 5.8 months (95% CI, 4.2-8.5) and 5.9 (95% CI, 5.5-7.6) per BICR and investigator review, respectively. In the subgroup analysis of ORR per BICR, which included patients from the overall adagrasib/cetuximab cohort, the ORR was 37% (95% CI, 25%-50%) in patients 65 years of age or younger vs 29% (95% CI, 14%-48%) in patients 65 years of age or older.

The median progression-free survival (PFS) was 6.9 months (95% CI, 5.6-7.4; 95% CI, 5.9-7.4) per both BICR and investigator review, respectively. Specifically, the 6- and 12-month PFS rates were 57% and 19%, respectively, per BICR; these rates were 61% and 19% per investigator review. The median overall survival (OS) in the population was 16 months (95% CI, 13.3-18.8), of which the 6- and 12-month OS rates per BlCR and investigator review were 88% and 66%, respectively.